TY - JOUR
T1 - Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index
AU - Faquih, Tariq O.
AU - Aziz, N. Ahmad
AU - Gardiner, Sarah L.
AU - Li-Gao, Ruifang
AU - de Mutsert, Renee
AU - Milaneschi, Yuri
AU - Trompet, Stella
AU - Jukema, J. Wouter
AU - Rosendaal, Frits R.
AU - van Hylckama Vlieg, Astrid
AU - van Dijk, Ko Willems
AU - Mook-Kanamori, Dennis O.
N1 - Funding Information: This study was supported by a VENI-grant (#91615080) from the Netherlands Organization of Scientific Research. N.A.A. is partly supported by an Alzheimer's Association Research Grant (Award Number: AARG-19-616534) and a European Research Council Starting Grant (Number: 101041677). The NEO study is supported by the participating Departments, Division, and Board of Directors of the Leiden University Medical Center, and by the Leiden University, Research Profile Area Vascular and Regenerative Medicine. DOM-K is supported by Dutch Science Organization (ZonMW-VENI Grant No. 916.14.023). T.O.F. was supported by the King Abdullah Scholarship Program and King Faisal Specialist Hospital & Research Center [No. 1012879283]. The infrastructure for the NESDA study ( www.nesda.nl ) is funded through the Geestkracht program of the Netherlands Organization for Health Research and Development (Grant No. 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ in Geest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Publisher Copyright: © 2023 The Author(s). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2023/5/15
Y1 - 2023/5/15
N2 - Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable - similar to those of higher risk of coronary artery disease and type 2 diabetes - and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.
AB - Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (<36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable - similar to those of higher risk of coronary artery disease and type 2 diabetes - and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.
UR - http://www.scopus.com/inward/record.url?scp=85167417390&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddad020
DO - https://doi.org/10.1093/hmg/ddad020
M3 - Article
C2 - 36715614
SN - 0964-6906
VL - 32
SP - 1741
EP - 1752
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 10
ER -